Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria

Mol Genet Metab. 2011 Aug;103(4):330-7. doi: 10.1016/j.ymgme.2011.04.012. Epub 2011 May 5.


Cystathionine beta-synthase (CBS) deficient homocystinuria (HCU) is an inherited metabolic defect that if untreated, typically results in cognitive impairment, connective tissue disturbances, atherosclerosis and thromboembolic disease. In recent years, chronic inappropriate expression of the inflammatory response has emerged as a major driving force of both thrombosis and atherosclerotic lesion development. We report here a characterization of the abnormalities in cytokine expression induced in both a mouse model of HCU and human subjects with the disease in the presence and absence of homocysteine lowering therapy. HCU mice exhibited highly significant induction of the pro-inflammatory cytokines Il-1alpha, Il-1beta and TNF-alpha. Similarly, in untreated/poorly compliant human subjects with HCU we observed constitutive induction of multiple pro-inflammatory cytokines (IL-1alpha, IL-6, TNF-alpha, Il-17 and IL-12(p70)) and chemotactic chemokines (fractalkine, MIP-1alpha and MIP-1beta) compared to normal controls. These HCU patients also exhibited significant induction of IL-9, TGF-alpha and G-CSF. The expression levels of anti-inflammatory cytokines were unaffected in both HCU mice and human subjects with the disease. In the human subjects, homocysteine lowering therapy was associated with either normalization or significant reduction of all of the pro-inflammatory cytokines and chemokines investigated. We conclude that HCU is a disease of chronic inflammation and that aberrant cytokine expression has the potential to contribute to multiple aspects of pathogenesis. Our findings indicate that anti-inflammatory strategies could serve as a useful adjuvant therapy for this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Betaine / pharmacology
  • Chemokine CCL4 / metabolism
  • Chemokines / metabolism*
  • Child
  • Child, Preschool
  • Cystathionine beta-Synthase / deficiency
  • Cystathionine beta-Synthase / genetics*
  • Cystathionine beta-Synthase / metabolism
  • Female
  • Homocystinuria / metabolism*
  • Homocystinuria / therapy
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-1alpha / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Tumor Necrosis Factor-alpha / metabolism


  • Chemokine CCL4
  • Chemokines
  • Interleukin-17
  • Interleukin-1alpha
  • Interleukin-1beta
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Betaine
  • Cystathionine beta-Synthase